Evidence presented in the journal The Lancet (Lancet 2025; 405: 648–57) have reported substantial benefits with improved visual acuity and functional vision following a treatment for a gene supplementation therapy for 4 young patients with variants of AIPL1-LCA4. Such patients with mutations in AIPL1-LCA4 cause severe and rapidly progressive impairment of sight from birth with congenital nystagmus, impaired pupil responses and severely reduced responses on electroretinography (ERG). The outcome of their open-label first-in-human interventional study was based in Moorfields Eye Hospital (London, UK) and Great Ormond Street Hospital for Children (London, UK). It was conducted in the absence of a clinical trial provided under a Specials Licence from the UK Medicines and Health products Regulatory Authority (MHRA) and with the approval of the Paediatric Bioethics Service at Great Ormond Street Hospital for Children, London, UK.
LCA is a severe congenital or early infant-onset form of non-syndromic retinal disease characterised by severe retinal dystrophy, vision loss, nystagmus, an absence of a normal pupil response and an almost non-recordable ERG. There are an estimated 26 different genes that have been implicated in LCA to date, with mutations in CEP290, GUCY2D, CRB1 and RPE65. LCA4 is an autosomal recessive disorder with mutations in the aryl-hydrocarbon receptor-interacting protein-like 1 (AILP1), located on chromosome 17p13.1. Variants in AIPL1 account for up to 5% of infants affected by early-onset rod-cone dystrophy and is expressed in rod and cone photoreceptor cells during development. Literature shows that the encoded protein “plays a crucial role in phototransduction acting as a specialised molecular co-chaperone for cGMP-specific PDE6, supporting the stability, assembly and catalytic activity of PDE6 in cones and rods.” In their current study in The Lancet, the gene supplementation study reported using a recombinant AAV vector comprising a human GRK1 promoter region driving the human AIPL1 coding sequence (rAAV8.hRKp.AIPL1). The experimental treatment was administered in one eye in each patient, at a titre of 1 × 10¹¹ vector genomes per mL during vitrectomy surgery under general anaesthesia, delivered sub-retinally.
Outcome measurements were assessed by visual acuity, functional vision, steady-state visual evoked potential (ssVEPs), and retinal structure (qualitative assessment of outer retinal lamination and apparent thickness). Visual acuity after intervention was compared with visual acuity before intervention and with the visual acuity of the untreated contralateral eye.
Figure 1: Methods to measure visual acuity and visual evoked potentials (A) The PopCSF test for visual acuity involves searching and touching (popping) moving Gabor patches (bubbles) with varying spatial frequencies, which can appear at any location on a tablet display.21 The physical spatial frequency of the gratings is adjusted dynamically for viewing distance through real-time head-tracking with the tablet’s front-facing TrueDepth camera. (B) data were collected by seating the participant in a comfortable chair at 55 cm from a 65° wide screen and presenting 2 s segments of time-varying (flickering) stimuli embedded in child-friendly cartoons. Our analysis focused on ssVEP responses to full-screen black-and-white flicker. ssVEP responses to grating stimuli with various spatial frequencies are in the appendix (pp 8–9). CSF=contrast sensitivity function. ssVEP=steady-state visual evoked potential. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), entitled: Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study, by Michaelides. M et al, Lancet 2025; 405: 648–57).
In their report in The Lancet, results showed that at a mean of 3.5 years (range 3.0-4.1) after intervention, the visual acuities of the treated eyes had improved to a mean of 0.9 logMAR (range 0.8-1.0), while visual acuities before the intervention were equivalent to 2.7 logMAR. In contrast, the visual acuities of the untreated eyes became unmeasurable at the final follow-up of the study. Compelling evidence of measurements, available through video recordings may be viewed through The Lancet paper: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02812-5/fulltext
In their report, researchers based in UCL Institute of Ophthalmology, University College London and the Centre and the Gene Therapy and Regenerative Medicine, King’s College, London, stated that their results was the first human clinical study to evaluate gene therapy for AIPL1-related retinal dystrophy. They commented that, “before intervention, the children’s visual function was limited to perception of light; all were legally blind from birth. 3–4 years after treatment, the visual acuities of their treated eyes had improved substantially. In contrast, the visual acuity of the children’s untreated contralateral eye showed no improvement.” Consequently, the clinicians are now administering sequential bilateral gene therapy to affected young children “under a Specials Licence and exploring the feasibility of making the product more widely available. This could mean an improvement in neurodevelopment and social behaviour and provide lifelong psychosocial benefit for children affected by this retinal dystrophy.”